Chorioamnionitis Dan PDA Survey

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RESEARCH ARTICLE

Chorioamnionitis and Patent Ductus

Arteriosus: A Systematic Review and Meta-Analysis

Hye Won Park1,2, Yong-Sung Choi3, Kyo Sun Kim1,2, Soo-Nyung Kim2,4*

1 Department of Pediatrics, Konkuk University Medical Center, Seoul, Korea, 2 Konkuk University School of

Medicine, Seoul, Korea, 3 Department of Pediatrics, Kyung Hee University School of Medicine, Seoul,

Korea, 4 Department of Obstetrics and Gynecology, Konkuk University Medical Center, Seoul, Korea

* [email protected]

Abstract

Background

Chorioamnionitis has recently been reported as a risk factor for various neonatal diseases,

including cerebral palsy, bronchopulmonary dysplasia, and necrotizing enterocolitis, but its

effect on patent ductus arteriosus (PDA) is unclear. We performed a systematic review and

meta-analysis to evaluate the effect of chorioamnionitis on PDA.

Methods

We searched PubMed, EMBASE, Cochrane Library, and KoreaMed databases using the

terms: intrauterine infectionormaternal infectionorantenatal infectionorchorioamnio

nitisorplacenta inflammationorplacenta pathologyorneonatal outcomeorneonatal

morbidityorPDA or patent ductus arteriosusorductus arteriosus,and prematurityor

very low birth weight infant.Studies were included if they were randomized controlled tri-

als, casecontrol studies, or cohort studies that included information relating to chorioam-

nionitis and PDA.

Results

Among 1,571 studies, a total of 23 studies (17,708 cases) were included in the meta-analy-

sis to analyze the relationship between chorioamnionitis and PDA, except one study that

only included PDA requiring surgical ligation. The association between chorioamnionitis

and PDA was statistically significant (odds ratio [OR] 1.43; 95% confidence interval [CI]1.19, 1.72; P < 0.0001). In subgroup analysis, clinical chorioamnionitis was not associated

with PDA (OR 1.28; 95% CI 1.00, 1.64, 1.790; P = 0.05), whereas histologic chorioamnioni-

tis (OR 1.54; 95% CI 1.10, 2.15; P = 0.01) and chorioamnionitis diagnosed from both clinica

and histologic findings (OR 1.75; 95% CI 1.07, 2.86; P = 0.03) showed significant associa-

tions with PDA. Chorioamnionitis did not increase the risk of PDA requiring surgical ligation

(OR 1.23; 95% CI 0.69, 2.17; P = 0.48), and antenatal steroid use reduced the risk of PDA

(OR 0.62; 95% CI 0.42, 0.90; P = 0.01) after chorioamnionitis.

PLOS ONE | DOI:10.1371/journal.pone.0138114 September 16, 2015 1 / 14

a11111

OPENACCESS

Citation:Park HW, Choi Y-S, Kim KS, Kim S-N

(2015) Chorioamnionitis and Patent Ductus

Arteriosus: A Systematic Review and Meta-Analysis.

PLoS ONE 10(9): e0138114. doi:10.1371/journal.

pone.0138114

Editor:Olivier Baud, Hpital Robert Debr, FRANCE

Received:May 4, 2015

Accepted:August 25, 2015

Published: September 16, 2015

Copyright: 2015 Park et al. This is an open

access article distributed under the terms of the

Creative Commons Attribution License, which permits

unrestricted use, distribution, and reproduction in any

medium, provided the original author and source arecredited.

Data Availability Statement:All relevant data are

within the paper and its Supporting Information files.

Funding:The authors have no support or funding to

report.

Competing Interests:The authors have declared

that no competing interests exist.
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Conclusions

The results from this meta-analysis support an association between maternal chorioamnio-

nitis and PDA in offspring.

Introduction

Chorioamnionitis is a risk factor for preterm birth, but the relationship between chorioamnio-

nitis and neonatal morbidity or mortality remains controversial. However, several meta-

analyses recently reported chorioamnionitis as a risk factor for various neonatal diseases, such

as cerebral palsy [1], retinopathy of prematurity [2], bronchopulmonary dysplasia [3], and nec

rotizing enterocolitis [4]. Although the routine treatment of patent ductus arteriosus (PDA) is

not recommended, persistent shunting through symptomatic PDA could increase the risk of

neonatal mortality and morbidity, including chronic lung disease, intraventricular hemor-

rhage, and necrotizing enterocolitis [5,6]. In the case of PDA, it has been reported that chor-

ioamnionitis was a risk factor for unresponsiveness to medical therapy with cyclooxygenase

inhibitors [7,8]. The effect of antenatal steroids after chorioamnionitis has been reported [ 9],

but the effect of chorioamnionitis itself on PDA occurrence is unclear. We performed a system-

atic review and meta-analysis to evaluate the effect of maternal chorioamnionitis on PDA in

offspring.

Materials and Methods

Search Strategy and Study Selection

We performed this meta-analysis in accordance with the PRISMA guidelines developed for

systematic reviews and meta-analyses (S1 PRISMA Checklist). We searched PubMed,

EMBASE, Cochrane Library, and KoreaMed databases using the terms: intrauterine infection

or

maternal infection

or

antenatal infection

or

chorioamnionitis

or

placenta inflamma-tionor placenta pathologyor neonatal outcomeor neonatal morbidityor PDAor

patent ductus arteriosusor ductus arteriosus,and prematurityor very low birth weight

infant.Manual searches were also performed on the reference lists of included studies and

other electronic databases. No restrictions were applied on language. The last search was per-

formed on September 19, 2014. The titles and abstracts of the articles were initially screened,

and the full-text articles were independently reviewed by two reviewers (HW Park and YS

Choi) using the selection criteria to determine inclusion in the meta-analysis.

Studies were included for meta-analysis if they met the following criteria: 1) study design:

randomized controlled trial, case-control study, or prospectively or retrospectively matched

cohort study; 2) patients: preterm infants who were born to a mother for whom information

about chorioamnionitis was available; 3) intervention: clinical or histologic chorioamnionitis;

and 4) outcomes: PDA (medically treated, surgically treated, or clinically diagnosed). Studieswere excluded from the meta-analysis if they were case reports, case series, or single-arm

cohort studies.

Data Extraction and Study Quality Assessment

Two authors (HW Park and YS Choi) independently reviewed the full text of all included stud-

ies and extracted data with a data extraction form. We extracted the following data: first author

publication year, study design, study location, study period, study population, definition of

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chorioamnionitis, definition of PDA, and incidence of PDA. We also extracted effect estimates,

odds ratios for the casecontrol studies, or relative risk for the cohort studies, along with the

corresponding confidence interval, from each of the studies.

Disagreements were resolved through interpretation by discussion with a third reviewer (KS

Kim). Methodological quality was independently assessed by two authors (HW Park and YS

Choi) using the NewcastleOttawa Scale for all included studies. This scale assesses study qual-

ity by evaluating three domains: selection (four items), comparability (one item), and out-

come/exposure (three items) for cohort studies and case-control studies, respectively. A study

that meets the criteria can be awarded a star, except for the comparability domain (which has a

maximum of two stars). The overall score is the total number of stars given, with a maximum

of 9. Overall scores of 04, 57, and 89 stars correspond to studies of low, moderate, and high

quality. Any disagreements between authors were resolved by discussion.

Data Synthesis and Statistical Analysis

We conducted a meta-analysis to generate pooled estimates for the association between mater-

nal chorioamnionitis and PDA in offspring using the RevMan 5.3.5 software (Cochrane

Library;http://tech.cochrane.org/revman/download) and Comprehensive Meta-Analysis Ver-

sion 3 (Biostat, Englewood, NJ, USA).Statistical heterogeneity was assessed using the I2 statistic (percentage of total variation

across studies), and I2>50% was used to detect significant heterogeneity. If there was no het-

erogeneity, the fixed effects model was used for the meta-analysis. A random effects model was

used for analysis if there was substantial statistical heterogeneity. A sensitivity analysis was con-

ducted to evaluate the robustness of the conclusion by removing each study sequentially and to

examine the effect of the elimination of each study on the pooled odds ratio (OR) results. A

cumulative analysis was performed to detect temporal trends by adding one study at a time

according to the year of publication.

Publication bias was assessed by the Begg and Mazumdar rank correlation test, the Egger s

regression test, and inspection of the funnel plot. A funnel plot and the Egger s regression test

were used to detect asymmetry based on the distribution of effect sizes against the standard

errors.

Results

Characteristics of the Included Studies

A total of 1,993 potentially relevant studies were identified from database searching, and 1,970

of them were excluded for the reasons listed inFig 1. After a complete survey of the literature,

we included 23 studies (21 cohort and 2 case-control studies) in the systematic review. The 23

eligible studies included in the meta-analysis [1032] examined a total of 17,708 mothers, of

whom 4,681 had chorioamnionitis and 13,027 did not.

The quality assessment of the included studies was performed using the Newcastle-Ottawa

Scale, and the results are presented inTable 1.

Six studies defined chorioamnionitis based on both clinical and histologic findings [15,18,

19,27,28,30]. In four studies[1013], chorioamnionitis was diagnosed based on clinical find-

ings, and the remaining 14 studies diagnosed it only on the basis of histologic findings of the

placenta (one of these was the study that only included surgical ligation [ 33]) [14,16,17,20

26,29,3133]. In cases of clinical chorioamnionitis, criteria that were used in most studies

were similar: the Gibbs criteria for chorioamnionitis [34], on the basis of maternal fever and

two or more of the following additional criteria: maternal tachycardia, fetal tachycardia, uterine

tenderness, foul odor of the amniotic fluid, and maternal leukocytosis. There were small

Chorioamnionitis and Ductus Arteriosus

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variations in diagnostic criteria, such as fever ( 38 or 38.3C), maternal leukocytosis

(> 12,000/mm3 or 15,000/mm3 or 18,000/mm3), and fetal tachycardia (heart rate > 160/min

or 180/min). In three studies, the elevation of C-reactive protein was included in the diagnostic

criteria [11,19,20]. Histologic chorioamnionitis was commonly diagnosed based on the infil-

tration of polymorphonuclear leukocytes in the placental membranes, including the Salfia cri-

teria [35], Blanc criteria [36], and criteria of the Amniotic Fluid Infection Nosology Committee

[37].

As a primary outcome, PDA was diagnosed in 5,284 of a total of 17,708 (30%) infants,

including 1,561 of 4,681 (33.3%) infants of a mother with chorioamnionitis and 3,723 of

13,027 (28.6%) infants of a mother without chorioamnionitis. Overall chorioamnionitis,

including that diagnosed based on clinical or histologic findings, was significantly associated

with PDA (OR 1.43; 95% CI 1.19, 1.72; P


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Table 1. Characteristics of studies included in this meta-analysis.

Study Location Study design Population Diagnosis, denition of PDA Qualityscore*

Histologic and clinical CA

Arayici 2014 Turkey Retrospectivecohort

GA 32 weeks and/orbirth weight 1,500 g

Echocardiography, size>1.5 mm, LA/aorta >1.5 and/or left-to-right shunting, end diastolic reversal of blood ow in

aorta

8

Been 2009 TheNetherlands

Prospectivecohort

GA 32 weeks Echocardiography 7

Erdemir 2013 Turkey Prospectivecohort

GA < 35 weeks NA 6

Mu 2008 Taiwan Prospectivecohort

birth weight 1,500 g Echocardiography, and clinical signs of PDA 7

Ogunyemi2003

USA Retrospectivecohort

GA, 2432 weeks NA 7

Seliga-Siwecka2013

Poland Prospectivecohort

GA < 32 weeks Echocardiography 6

Clinical CA

Barrera-Reyes2011

Mexico Prospectivecohort

GA < 34 weeks and birthweight< 1,500 g

NA 8

Botet 2010 Spain Casecontrol birth weight< 1,500 g Presence of PDA (including surgical ligation) 8

Garcia-Munoz2014

Spain Prospectivecohort

birth weight < 1,500 g Echocardiography, requiring treatment (medical or surgical) 7

Soraisham2009

Canada Prospectivecohort

GA < 33 weeks Clinical signs and requiring treatment (medical or surgical) 7

Histologic CA

Ahn 2012 Korea Prospectivecohort

GA < 34 weeks Echocardiography, requiring treatment (medical or surgical) 8

De Felice 2005 Italy Prospectivecohort

Birth weight 1,500 g NA 6

Dessardo 2012 Croatia Prospectivecohort

GA < 32 weeks Echocardiography, and clinical signs of PDA 7

Ecevit 2014 Turkey Retrospective

cohort

GA < 37 weeks NA 6

Elimian 2000 USA Retrospectivecohort

Birth weight, 5001,750g

PDA requir ing treatment (medical or surgical) 7

Hendson 2011 Canada Prospectivecohort

GA 32 weeks andbirth weight 1,250 g

Clinical diagnosis or radiologic diagnosis 6

Liu 2014 China Prospectivecohort

GA 34 weeks Echocardiography, and clinical symptoms of PDA 7

Perrone 2012 Italy Prospectivecohort

GA, 2331 weeks Echocardiography, size>1.4 mm/kg body weight, LA/aorta>1.4, LA enlargement, shunting, end diastolic reversal of

bloodow in descending aorta

6

Prendergast2011

UK Prospectivecohort

GA 32 weeks Requiring treatment (medical or surgical) 5

Rocha 2006 Portugal Retrospectivecohort

GA 34 weeks Echocardiography 8

Sato 2011 Japan Retrospectivecohort GA

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